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Category: genetics

Hearing research traces evolution of key inner ear protein

In the intricate machinery of the inner ear, hearing begins with a protein that moves a few billionths of a meter up to 100,000 times per second. That protein, called TMC1, sits at the tips of sensory hair cells deep in the snail-shaped cochlea. When sound waves move these microscopic hairs, TMC1 acts as a channel, opening and allowing charged particles to flow into the cell and trigger an electrical signal to the brain.

Without TMC1, that signal never starts. Mutations in the TMC1 gene are a well-known cause of hereditary hearing loss in humans. Because of this central role, TMC1 is an attractive target for researchers designing gene therapies aimed at restoring hearing. Several groups are testing ways to supply working copies of the gene or fix harmful mutations.

For these efforts to be safe and effective, scientists need to know in detail how TMC1 is built, how it opens, and which parts of the protein are most sensitive to change. However, the hair-cell system that includes TMC1 is so complex, sensitive, and hard to access that it is notoriously difficult to take apart and study directly.

Why no individual is like another when epigenetics come into play

Why do animals behave differently, and what are the consequences of this? A research team from the Collaborative Research Center NC³ at Bielefeld University and the University of Münster now provides a new explanation: epigenetic processes—chemical markings on DNA—may play a key role. The study, published in the journal Trends in Ecology & Evolution, links individuality, environmental adaptation, genetics, ecology, and evolution in a novel way.

“With our study, we propose that individuality and epigenetic variation influence each other,” explains Dr. Denis Meuthen, an evolutionary biologist at Bielefeld University, who is one of the study’s main authors. “This bidirectionality—this mutual interaction—helps us to better understand ecological and evolutionary processes.”

RNA-guided CRISPR system activates gene expression

In back-to-back studies published in Nature, researchers from Purdue University and Columbia University report a naturally evolved gene-editing system that can activate genes, offering an advantage over existing CRISPR gene-editing systems that merely find and cut DNA. The research includes two complementary studies, one examining the biological function of the system and the other revealing the molecular mechanism that enables it.

The team’s research on a variant of the CRISPR—Clustered Regularly Interspaced Short Palindromic Repeats—system broadens understanding of CRISPR’s natural diversity and provides a foundation for new gene-regulation technologies. Because this CRISPR variant activates genes without cutting DNA, it could be adapted for precise gene control applications, including research tools and potential therapeutic strategies that turn on genes without permanently altering the genome.

One study shows that this CRISPR system, using a strand of RNA as a guide, finds specific sections of DNA, known as genes, and attracts the cell’s own gene expression machinery to the location to activate the gene. The second study explains how the molecular complex performs this task, revealing how its structure allows it to recruit RNA polymerase—the enzyme responsible for transcribing DNA into RNA—to initiate gene expression.

Protein modification discovery opens cancer therapy possibilities

A research team led by Purdue University’s W. Andy Tao has discovered a new type of protein modification related to cellular mutation that impairs a crucial enzyme’s ability to help drive energy processes. Their discovery, published in Nature Chemistry, opens a new route to therapeutic cancer intervention.

“Mutation is considered the driving mechanism leading to cancer. Many mutations are hidden and harmless, but the mutation of enzymes like kinases can lead to the uncontrolled growth of cancer cells,” said Tao, a professor of biochemistry in Purdue’s College of Agriculture.

The study wades into the interactive dynamic complexity of the human genome (containing 20,000 to 25,000 genes) and the human proteome (containing more than 1 million proteins). The researchers identified a new modification on proteins because of the mutation in the isocitrate dehydrogenase (IDH) enzyme, which affects how kinase enzymes control protein function.

Early Clinical and EEG Association of Genotype and Outcome in Genetic EpilepsiesA Cohort Study and Hierarchical Clustering Analysis

This study analyzed a large cohort of patients with genetic epilepsies using hierarchical clustering analysis to identify homogeneous subgroups defined by specific genetic causes, each showing distinct clinical and EEG patterns.

We included 277 patients (52.3% female; median age at last follow-up 8.1 years, range 0–40). Drug resistance occurred in 58.8% and severe DD/ID in 35.4% of patients. EEG data at onset were available for 107 individuals. Neonatal onset was associated with a higher rate of drug resistance (71.4%; odds ratio [OR] 2.0, 95% CI 1.05–3.77), movement disorders (60.7%; OR 3.7, 95% CI 2.02–6.82), and severe DD/ID (71.4%; OR 7.0, 95% CI 3.66–13.49). Slow EEG background activity and multifocal epileptiform discharges were associated with both drug resistance and severe DD/ID. HCA identified genotype-phenotype groupings, including clusters involving SCN1A, PRRT2, STXBP1, KCNQ2, SCN2A, CHD2, SYNGAP1, and MECP2, each linked to specific clinical and EEG features.

New computational biology for genome sequencing analysis

To improve the ability of metapipeline-DNA to determine where changes in the genome have occurred, the scientists worked with the Genome in a Bottle Consortium led by the U.S. Department of Commerce’s National Institute of Standards and Technology. By incorporating this public-private-academic consortium’s meticulously validated resources, the researchers reduced the rate of false positives without reducing the tool’s precision in finding true genetic variants.

The researchers also produced two case studies demonstrating the pipeline’s capabilities for cancer research. The investigators used metapipeline-DNA to analyze sequencing data from five patients that donated both normal tissue and tumor samples, as well as another five from The Cancer Genome Atlas.

The next step is to get metapipeline-DNA into more labs to accelerate discoveries, and to continue improving the resource with more user feedback. ScienceMission sciencenewshighlights.

In a single experiment, scientists can decipher the entire genomes of many patient samples, animal models or cultured cells. To fully realize the potential to study biology at this unprecedented scale, researchers must be equipped to analyze the titanic troves of data generated by these new methods.

Scientists published findings in Cell Reports Methods discussing building and testing a new computational tool for tackling massive and complex sequencing datasets. The new resource, named metapipeline-DNA, may also make sequencing data analysis more standardized across different research labs.

The sequence of a single human genome represents about 100 gigabytes of raw data, the rough equivalent of 20,000 smartphone photos. The sheer scale of experimental data increases significantly as tens or hundreds of genomes are added into the mix.

Continue reading “New computational biology for genome sequencing analysis” | >

Uncovering the evolutionary limits of the COVID-19 virus

A new paper in Genome Biology and Evolution, indicates that while the COVID-19 virus has developed rapidly since 2019, it has done so within limited genetic channels. These genetic limits have remained unchanged. Despite scientists’ earlier fears about dramatic, rapid evolution of the COVID-19 virus, it appears recent changes in the virus were relatively constrained; the virus altered by combining pre-existing mutations. The virus has not expanded the number of genetic routes it can take to evolve.

The paper is titled “Structural constraints acting on the SARS-CoV-2 spike protein reveal limited space for viral adaptation.”

Novel Octameric Resistosome and Immune Mechanism in Wheat

After activation, these NLRs form multi-protein complexes—called resistosomes—that carry out the immune response. Studies have shown that certain resistosomes are pentameric (e.g., ZAR1 and Sr35), whereas others are hexameric (e.g., NRC2 and NRC4). These complexes initiate immune responses by triggering calcium (Ca2+) influx into the cytoplasm. However, the G10 type of CC-NLR (CCG10-NLR) immune receptors constitutes a unique clade among CC-NLRs and its activation mechanism has remained poorly understood.

Now, in a study published in Cell, a research team has revealed a novel octameric resistosome formed by an activated wheat CCG10-NLR immune receptor, which induces Ca2+ influx and immune responses through a unique channel architecture.

The researchers identified the Wheat Autoimmunity 3 (WAI3) gene, which encodes a CCG10-NLR protein. Subsequent analysis revealed that a gain-of-function (GOF) single amino acid mutation in the leucine-rich repeat (LRR) domain leads to autoactivation, providing an opportunity to study the activation mechanism of CCG10-NLR.

After expressing the WAI3 proteins in Nicotiana benthamiana, the researchers used cryo-electron microscopy to resolve the octameric structure of the activated WAI3 resistosome—marking the first time an octameric resistosome has been identified in plants.

The CCG10-NLR WAI3 resistosome differs from known resistosomes both in the number of monomers and in its conformation, representing a novel assembly mechanism for plant NLR resistosomes.

Using Nicotiana benthamiana and animal cell expression systems, the researchers also demonstrated that the WAI3 resistosome induces Ca2+ influx in plants but is not effective in animal cells. ScienceMission sciencenewshighlights.

Continue reading “Novel Octameric Resistosome and Immune Mechanism in Wheat” | >

The Jellies That Evolved a Different Way To Keep Time

Developmental biologist Tsuyoshi Momose cultures a newly discovered species of jellyfish in a tank of circulating water. Scientists want to understand how these unusual jellies keep time.

The passage of the sun across the sky — dawn, day, dusk, night — drives the clock of life. Some species wake with the sun and sleep with the moon. Others do the opposite, and a few keep odd hours. These naturally driven, 24-hour biological cycles are known as circadian rhythms, and they do more than cue bedtime: They regulate hormones, metabolism, DNA repair, and more. When life falls out of sync, there can be dire consequences for health, reproduction, and survival.

Lacking watches, many species keep time using an internal system — a set of interacting genes and their protein products that effectively keeps track of a 24-hour period — that is calibrated by sunlight. This kind of circadian clock is widespread, found even in single-celled algae, which suggests that biological timekeeping evolved billions of years ago. Across animals, most species have the same genetic system, using genes known as CLOCK, BMAL1, and CRY, or recognizable homologues. This form of biological clock mechanism appears even in ancient lineages, including sponges and some jellyfish.

But is this the only way to do it? In a pea-size jelly off the coast of Japan, biologists are examining a different kind of timekeeping.

Protein atlas connects the biological dots underlying neurodegenerative diseases

Neurodegenerative diseases form a tangled biological web with overlapping molecular signatures and symptoms. To decode this complexity, a multi-institute collaboration led by St. Jude Children’s Research Hospital scientists developed the pan-neurodegeneration atlas (PanNDA). The atlas is a comprehensive survey of neurodegenerative disease “proteomes” containing information about protein levels, modifications, and interactions. This resource, published today in Cell, provides a wide-ranging protein-based outlook to better understand the origins of neurodegenerative diseases and to aid in their diagnosis and treatment.

Neurodegenerative diseases often stem from protein misfolding or accumulation. These errors also disrupt binding partners, upstream and downstream effectors, and any connected pathways. By combining multiple proteomic strategies, co-corresponding authors Junmin Peng, Ph.D., St. Jude Departments of Structural Biology and Developmental Neurobiology, and Bin Zhang, Ph.D., Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, created PanNDA to understand and explore this network and how it is disrupted in these diseases.

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